Addiction Biology最新文献

GPR88, an orphan G protein-coupled receptor primarily expressed in the striatum, has emerged as a potential target for treating alcohol use disorder (AUD) due to its role in modulating reward and motivational pathways. In this study, we investigated the effects of the GPR88 agonist RTI-122 on alcohol intake and motivation to self-administer alcohol under different conditions. In mice, RTI-122 reduced alcohol consumption in a two-bottle choice paradigm, which was prevented by Gpr88 knockout, confirming a GPR88-specific effect on the attenuation of alcohol drinking. In rats, RTI-122 dose-dependently reduced operant alcohol self-administration and decreased motivation to self-administer alcohol in progressive ratio tasks, regardless of whether the alcohol was adulterated with quinine or not. Additionally, a high dose of RTI-122 reduced yohimbine-induced reinstatement. Importantly, RTI-122 did not affect water intake in mice or sucrose self-administration in rats, indicating receptor- and reward-specific modulation of alcohol intake. These findings suggest that RTI-122, through GPR88 agonism, effectively reduces alcohol consumption and motivation across various contexts, positioning it as a promising lead for the development of new AUD treatments.

Opioid agonists are known for their effects on the opioid and dopaminergic systems; however, new research points to complementary changes in the gut underlying maladaptive changes associated with opioid use. The gut–brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders, but the spatiotemporal correspondence between quantitative translational measures of gut and brain health is not clear. In this work, we determined longitudinal and concurrent changes in the brain and gut of rodents trained to self-administer morphine for 14 days. Active lever presses delivered a single infusion of morphine (0.4 mg/kg/infusion). We used MRI and 16s rDNA analysis of faecal matter to identify changes from baseline (naïve, nondrug state) to an acute phase (early in the self-administration process, after 2 days of self-administration) and a chronic phase (late in the self-administration process, after 14 days of self-administration). Animals were scanned in a 7T MRI scanner three times (baseline, acute and chronic), and before scanning, faecal matter was collected from each rat. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum and thalamus. We posit that gut changes precede the effects observed in MRI, with the striatum and thalamus emerging as crucial links mediating communication between the gut and the brain.

Substance use disorder constitutes a global health challenge. Preclinical investigations into addiction heavily rely on animal models to explore the underlying biological mechanisms of addictive disorders, with a particular emphasis on understanding the etiological factors influencing drug intake. Exploring sex differences across various phases of addiction has revealed a heightened vulnerability in females. This study systematically reviews the impact of ovarian hormones on the consumption of psychoactive substances in rodents, adhering to the PRISMA 2009 protocol. Our findings underscore the significant role of ovarian hormones, particularly oestrogen, in augmenting drug consumption among female rodents. Notably, with heroin, it was observed that progesterone, rather than oestrogen, facilitated increased consumption in female rodents. The susceptibility to addiction influenced by oestrogen is accentuated across distinct phases, and the molecular mechanisms form a complex interplay that significantly influences addictive behaviours. By bringing together these findings, we aim to establish a strong foundation for future studies. This work may guide clinical investigations in developing more effective prevention or treatment strategies that address the unique vulnerabilities of females to substance use disorders.

A recent study by Hakus et al. (2025) demonstrated sex-associated differences in Pavlovian phenotypes in rodents, with females more likely to exhibit sign-tracking behaviour and males more likely to exhibit goal-tracking behaviour. In the present work, we provide evidence that similar patterns emerge in humans. Using a validated eye-tracking procedure in a Pavlovian learning paradigm, we show that women are more frequently classified as sign-trackers and quantitatively show greater sign-tracking behaviour than men in a large human sample. These results support the translational value of preclinical findings and highlight the importance of considering sex differences in incentive salience attribution. Given the established link between sign-trackers and addiction vulnerability, our findings may help refine our understanding of individual risk factors in the development of such disorders.

Opioid abuse is a severe global health challenge, leading to rising morbidity, mortality, and increasing societal costs. The aim of this study was to investigate neuroinflammation, neuronal damage and potential changes in the orexin system or beta-amyloid metabolism in the cerebrospinal fluid (CSF) of individuals undergoing opioid substitution therapy (OST). This cross-sectional study investigates CSF biomarkers in individuals undergoing OST, compared to control subjects. Participants receiving OST were recruited from the outpatient clinic at the Department of Psychiatry, Sahlgrenska University Hospital, Gothenburg (Sweden). Each participant provided a complete medical history, including details of drug use over the past 6 months, followed by a lumbar puncture to obtain CSF samples. Molecules associated with neuroinflammation, neuronal and glial damage, beta-amyloid metabolism and orexinergic function were analysed in the participants' CSF, alongside electrolyte levels. Specifically, we analysed levels of sTREM-2, YKL-40, IL-1β, IL-6, IL-8, IL-10, TNF-α, AXL, MER, TYRO3, GAS6, NfL, GFAP, total tau (T-tau), phosphorylated tau (P-tau), neurogranin, Aβ40, Aβ42, the Aβ42/Aβ40 ratio, orexin-A, sPDGFR-β and electrolytes. The study included 15 control subjects and 17 in the opioid substitution group. Patients undergoing opioid substitution therapy exhibited elevated levels of sTREM-2, Aβ42/Aβ40 ratio and NfL in their CSF. Conversely, concentrations of Na⁺ and Cl⁻ were lower compared to controls. No significant differences were found between groups for other biomarkers, including orexin-A. However, when normalized to Aβ40 levels, YKL-40, IL-8, TYRO3 and P-Tau were also elevated in individuals with opioid dependence. Elevated biomarkers of neuroimmune activation, neuronal damage and beta-amyloid metabolism in opioid dependence suggest CNS inflammation as a contributor to its pathophysiology. Reduced electrolyte levels imply disrupted CSF water regulation, possibly linked to impaired glial function. These findings highlight both neural and non-neural mechanisms in opioid dependence.

Over 10% of the US population over 12 years old meets criteria for alcohol use disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3-beta (GSK3β) has been implicated in ethanol behaviours and poses as a potential therapeutic target in the treatment of AUD. Here, we investigated the preclinical evidence for tideglusib, a clinically available selective GSK3β inhibitor, in modulating chronic and binge ethanol consumption. Tideglusib decreased ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behaviour (drinking in the dark) without effecting water intake. With drinking in the dark, tideglusib was more potent in males (ED50 = 64.6, CI = 58.9–70.8) than females (ED50 = 79.4, CI = 70.8–93.3). Further, we found tideglusib had no effect on ethanol pharmacokinetics, taste preference or anxiety-like behaviour, although there was a transient increase in total locomotion following treatment. Additionally, tideglusib treatment did not alter liver function as measured by serum activity of alanine aminotransferase and aspartate aminotransferase but did cause a decrease in serum alkaline phosphatase activity. RNA sequencing analysis of tideglusib actions on ethanol consumption revealed alterations in genes involved in synaptic plasticity and transmission, as well as genes downstream of the canonical Wnt signalling pathway, suggesting tideglusib may modulate ethanol consumption via β-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3β in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.

Tobacco use causes more than 8 million deaths globally each year, and the number of younger smokers is growing. It is of great practical importance to explore the underlying neural mechanisms behind the behaviour of young smokers. During cue-induced craving, reward system in the brain generates neural oscillations at specific frequencies. The phase–amplitude coupling (PAC) can capture interactions between these frequencies and may be a more sensitive quantitative indicator for characterizing abnormal neural oscillations in smokers. We monitored the electroencephalography (EEG) data of 30 young smokers during a cue task after 12 h of abstinence, dividing the data into the neutral and smoking-related groups based on different experimental stimuli to analyse the relationship between PAC and craving. In addition, we computed the functional connectivity (FC) under the PAC mechanism. The results showed that the young smokers exposed to smoking-related cues under short-term abstinence conditions had significantly lower PAC values and reduced FC strength in the right prefrontal cortex. In contrast, there was a significant increase in PAC values in the parietal cortex and enhanced FC strength. The correlation analysis showed significant correlations between PAC values and craving. These findings demonstrate for the first time that PAC abnormalities in young smokers exposed to smoking-related cues under short-term abstinence conditions may be related to craving and inhibitory control.

Cannabis is one of the most commonly used illicit drugs worldwide, with its prolonged use potentially leading to various cognitive impairments and brain structural changes. However, current research on the dynamic changes in cortical thickness (CT) related to cannabis use remains limited, especially regarding the relationship between the severity of cannabis use and CT changes in heavy cannabis use (HCU). This study employed a longitudinal design to investigate CT changes in young adults with HCU from baseline (BL) to 3-year follow-up (FU). The results showed a significant group effect in the left lateral orbitofrontal cortex (OFC), and a significant time effect revealed CT changes in several brain regions, including the left lateral frontal cortex, bilateral medial frontal cortex, bilateral posterior cingulate cortex and bilateral insula. Simple effects analysis further demonstrated that the CT of left lateral OFC in young adults with HCU decreased significantly at FU compared with their BL and was also lower than control group at FU. Furthermore, a significant positive correlation was observed between the total score of Cannabis Use Disorders Identification Test at FU and the CT of left lateral OFC. These findings suggest that prolonged cannabis use may disrupt the structural integrity of the left lateral OFC, impairing decision-making, impulse control and emotional processing, thereby exacerbating addictive behaviours. This study provides key evidence for understanding the neural mechanisms underlying cannabis addiction.